PROJECT SUMMARY Flexible decision-making, a form of cognitive/behavioral plasticity, is important for adapting to changing demands and circumstances in the world. The devaluation task is an animal model used to investigate the neuronal substrates of flexible decision-making. Laboratory models of decision-making using the devaluation task limit the response options available and the cues indicating the outcomes of these responses. However, the individual brain areas involved in devaluation are highly dependent on the model task used, and this simplification of the task can lead to versions of the devaluation task not requiring certain brain areas that are activated in human devaluation experiments and that are required for flexible human decision-making. The proposed research will validate that a task that is more similar to the human decision-making environment, with its multiple-response contingencies and cues that signal the contingencies, can be used to investigate the neural circuits of devaluation. One specific aim will investigate a devaluation task that more closely resembles human decision- making to ensure that it is sensitive to inactivation during learning of three key brain areas involved in flexible decision-making in humans, the basolateral amygdala (BLA), mediodorsal thalamus (MD), and orbitofrontal cortex (OFC). A second aim will then investigate whether interactions between these brain areas are necessary for learning the information necessary for the devaluation task. We will selectively inactivate connections between MD and the other two brain areas with microinjections of a chemogenetic virus (selectively activated by a normally inert ligand) into one brain area and microinjections of the ligand into a second brain area. The third aim will also determine whether these brains areas communicate with one another through direct projection by combining retrograde tracer injections into OFC with the neuronal activity marker Fos after a devaluation test. This will determine if the neurons in BLA and MD that project to OFC are the same neurons that are active during a devaluation test. The effects of disrupting BLA function on neuronal communication between MD and OFC will also be investigated. The results of these experiments will be potentially significant for understanding the brain circuitry that is responsible for adaptive and maladaptive plasticity that can lead to human decision-making function and dysfunction. Determining the exact nature of the neurobiological circuits for decision-making will promote the further development of targeted therapeutic techniques to mitigate decision-making impairments that could result from injuries, exposure to drugs of abuse or other toxins, genetic disorders, or other developmental problems. The project?s strong emphasis on examining the circuits-level plasticity that occurs during learning, and how alterations in this plasticity can have a detrimental effect on later goal-directed action, will also advance the C-NAP mission, enhancing the cross-cutting C-NAP research theme of the neurobiology of reward and decision.